From the AGA Journals

H. pylori antibiotic resistance reaches ‘alarming levels’

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New treatment guidelines are needed

The first-line treatment of individuals with Helicobacter pylori infection using clarithromycin-based triple therapies or, if penicillin allergic, bismuth-based quadruple therapies is generally effective. However, reports of declining therapeutic efficacy have led to published guidelines to recommend confirmation of H. pylori eradication after completing a course of antibiotics. It is believed that increasing antibiotic use in agriculture and medicine around the globe have contributed to the increasing H. pylori antibiotic resistance and declining efficacy of standard H. pylori regimens.

Dr. John Y. Kao

Savoldi et al. performed a systematic review and meta-analysis to assess the distribution of H. pylori resistance to commonly used antibiotics and to measure the association between antibiotic resistance and treatment failure over the past 10 years. They found alarming trends of increasing antibiotic resistance globally that correlated with rising rates of treatment failure. The authors recommend establishing local antibiotic resistance surveillance networks to guide clinical decisions in selecting effective antibiotic regimens.

Indeed, most H. pylori guidelines recommend antibiotic sensitivity testing after failing two courses of treatment; however, performing such testing successfully may require sending fresh gastric biopsy samples to an in-house H. pylori culture lab within 1 hour, which is generally not available to most clinicians. Clearly, the gap in knowledge of local antibiotic resistance could be addressed by having a readily accessible culture facility and the testing should be reimbursed by health insurance.

Single-center experiences with antibiotic sensitivity–guided salvage therapy in the United States, however, registered a lower efficacy rate of approximately 50%, which indicates that other host factors (such as gastric acidity pH less than 5.5 or body mass index greater than 30 kg/m2) may affect the minimum inhibitory concentration (MIC) of the antibiotics against H. pylori.

In order to better study the effects of these host factors relative to the effect of antibiotic resistance on therapeutic efficacy, it is critical that we practice precision medicine by determining the antibiotic sensitivity of the H. pylori strain prior to initiating the antibiotic treatment. It may be possible to achieve more than 90% therapeutic efficacy given known antibiotic sensitivities of the bacteria and optimized host factors to lower the MIC. In addition, with the increasing awareness of the importance of gut microbiota in health and disease, clinicians should strive to narrow the antibiotic coverage that will be possible if antibiotic sensitivity is known (for example, use high-dose amoxicillin and proton-pump inhibitor dual therapy).

John Y. Kao, MD, AGAF, is the current chair of the AGA Institute Council Esophageal, Gastric and Duodenal Disorders Section, a physician investigator in the University of Michigan Center for Gastrointestinal Research, and an associate professor in the department of medicine in the division of gastroenterology & hepatology and an associate program director of the GI Fellowship Program at Michigan Medicine at the University of Michigan, Ann Arbor. He has no conflicts.



Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

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The prevalence of primary clarithromycin resistance exceeded 15% in the WHO European Region (18%; 95% confidence interval, 16%-20%), the Eastern Mediterranean Region (33%), and the Western Pacific Region (34%) and reached 10% in the Americas and the South East Asia region. Furthermore, primary resistance to metronidazole exceeded 15% in all WHO regions, ranging from 56% in the Eastern Mediterranean Region to 23% in the Americas. Resistance to levofloxacin was at least 15% in all WHO regions except the European region (11%).

In most regions, H. pylori also accrued substantially more antimicrobial resistance over time, the investigators said. Clarithromycin resistance rose from 13% during 2006 through 2008 to 21% during 2012 through 2016 (P less than .001). Levofloxacin resistance in the Western Pacific region increased from 12% to 31% during the same two time periods (P less than .001). Several other WHO regions showed less significant trends toward increasing resistance. Multidrug resistance also rose. Resistance to both clarithromycin and metronidazole increased markedly in all WHO areas with available data, reaching 14% in the Eastern Mediterranean and Western Pacific regions and 23% in the European region.

Secondary analyses linked resistance with dramatic increases in the odds of treatment failure. For example, clarithromycin resistance conferred a sevenfold increase in the odds of treatment failure for regimens containing clarithromycin (odds ratio, 7.0; 95% CI, 5.2 to 9.3; P less than .001). Corresponding ORs were 8.2 for levofloxacin resistance, 2.5 for metronidazole resistance, and 9.4 for dual clarithromycin-metronidazole resistance.

The investigators acknowledged several limitations. Of publications in this meta-analysis, 85% represented single-center studies with limited sample sizes, they wrote. Studies often excluded demographic and endoscopic details. Furthermore, only three studies provided prevalence data for the WHO Africa Region and these only provided overall estimates without stratifying by resistance type.

The German Center for Infection Research, Clinical Research Unit, and the WHO Priority List Pathogens project helped fund the work. One coinvestigator disclosed ties to RedHill Biopharma, BioGaia, and Takeda related to novel H. pylori therapies.

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

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